(-)-Epigallocatechin-3-gallate (EGCG) is a component of green tea, a widely used herbal remedy. Green tea has been consumed for its health benefits for thousands of years, yet the molecular mechanism by which EGCG mediates its effects is not fully understood. EGCG has been intensively studied for its anti-cancer effects. EGCG inhibits the proliferation and induces apoptosis in many types of cancer lines. Several EGCG-binding proteins have been identified, and a subset of these has been shown to mediate the pro- apoptotic effects of EGCG in different cell lines. However, EGCG also has potent and potentially medically useful effects on neurons. EGCG prevents neuronal cell death in various models of neurodegenerative disease as well as in excitotoxicity models. Additionally, EGCG is able to inhibit the effects of certain molecules, such as Semaphorin 3A (SemaSA), that promote axonal retraction. This effect could make EGCG useful as a CAM for disorders such as spinal cord injury or other traumatic nerve injuries. However, it is unknown if the receptors that mediate the antiapoptotic effects of EGCG also mediate the effects of EGCG on neurons. Alternatively, other EGCG-proteins, such as squalene monooxygenase, MICAL, or 67LR might mediate the effects of EGCG in neurons. To identify the mechanisms by which EGCG mediates its effects in neurons, the specific aims of this proposal are: (1) To develop reagents and assay candidate EGCG receptors for neuroprotection. In this aim, I describe experiments to ascertain if siRNA-mediated knockdown of the putative EGCG receptors phenocopies the effect of EGCG treatment in an assay for neuronal excitotoxicity using cultured rat hippocampal neurons;and (2) To determine whether candidate EGCG receptors mediate the effects of EGCG on axons. In this aim, I describe experiments using knockout and overexpression strategies to determine if known EGCG-binding proteins mediate the ability of EGCG to block SemaSA signaling in axons. Together, the experiments in these two aims will clarify whether the putative EGCG receptors mediate the well-documented actions of EGCG in neurons. Because of the widespread consumption of EGCG, the identification of biologically relevant EGCG receptors is important for understanding the mechanism of action, appropriateness, and safety of EGCG dietary supplementation. Additionally, the identification of biologically relevant receptors for the actions of EGCG in neurons will help to clarify the suitability of EGCG as a CAM for neurological diseases and disorders associated with nerve injury.